In the spine, the epidural space (also known as “extradural space” or “peridural space”) is the outermost part of the spinal canal. It is the space within the canal (formed by the surrounding vertebrae) lying outside the dura mater (which encloses the arachnoid mater, subarachnoid space, the cerebrospinal fluid, and the spinal cord). In humans, the epidural space contains lymphatics, spinal nerve roots, loose fatty tissue, small arteries, and a network of large, thin-walled blood vessels called the epidural venous plexus.
An epidural steroid injection is a minimally invasive procedure that can help relieve neck, arm, back, and leg pain in an individual caused by inflamed spinal nerves. For instance, an epidural steroid injection may be performed to relieve pain caused by spinal stenosis, spondylolysis, or disc herniation in an individual. Medicines are delivered to the spinal nerve through the epidural space, the area between the protective covering (dura) of the spinal cord and vertebrae. Corticosteroid injections can reduce inflammation and can be effective when delivered directly into the painful area of the individual.
The goal of an epidural steroid injection is to place the medication near the area of injury and/or pathology within the spine. Interlaminar, caudal, and transforaminal injections are typically used for epidural steroid injections. An interlaminar epidural injection is performed by placing a needle between the bony vertebrae in the epidural space, followed by injection of medicine. A caudal injection is an injection into the lowest portion of the epidural space, into the area between the membrane that contains the spinal fluid and the thickest ligament between vertebrae. A transforaminal injection is an injection into the opening (also known as a foramen) at the side of the spine where a nerve roots exits.
Prednisolone is a cortico steroid drug with predominant glucocorticoid and low mineralocorticoid activity, making it useful for the treatment of a wide range of inflammatory and auto-immune conditions such as asthma, uveitis, pyoderma gangrenosum, rheumatoid arthritis, ulcerative colitis, temporal arteritis and Crohn's disease, Bell's palsy, multiple sclerosis, cluster headaches, vasculitis, acute lymphoblastic leukemia and autoimmune hepatitis, systemic lupus erythematosus, Kawasaki disease and dermatomyositis.
Methylprednisolone is typically used for its anti-inflammatory effects. The list of medical conditions for which methylprednisolone is prescribed is rather long, and is similar to other corticosteroids such as prednisolone. Common uses include arthritis therapy and short-term treatment of bronchial inflammation or acute bronchitis due to various respiratory diseases. It is used both in the treatment of acute periods and long-term management of autoimmune diseases, most notably systemic lupus erythematosus. It is also used as a treatment for multiple sclerosis.
Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid drugs. It acts as an anti-inflammatory and immunosuppressant. Dexamethasone is used to treat many inflammatory and autoimmune conditions, such as rheumatoid arthritis and bronchospasm. Dexamethasone may also be used to treat idiopathic thrombocytopenic purpura, which is a decreased number of platelets due to an immune problem.
Triamcinolone acetonide is a synthetic corticosteroid with marked anti-inflammatory action. KENALOG®-10 Injection (triamcinolone acetonide injectable suspension, USP) is triamcinolone acetonide, in a sterile aqueous suspension suitable for intralesional and intra-articular injection, and not suitable for intravenous, intramuscular, intraocular, epidural, or intrathecal use. Each mL of the sterile aqueous suspension provides 10 mg triamcinolone acetonide, with sodium chloride for isotonicity, 0.9% (w/v) benzyl alcohol as preservative, 0.75% carboxymethylcellulose sodium, and 0.04% polysorbate 80; sodium hydroxide or hydrochloric acid may have been added to adjust pH between 5.0 and 7.5.
Existing pharmaceutical compositions may have immediate or short-term effects on alleviating pain. This may be sufficient for purposes of short-term administration such as to overcome an acute episode or exacerbation of pain. However, such formulations may require repeated administration, especially for sustained or chronic pain. In addition, for localized pain, epidural injections that result in the diffusion of the active ingredient outside of the target area may be undesirable and may increase the need for an overall higher dose to ensure that the target area is exposed to an effective dose. Furthermore, pharmaceutical compositions and methods of administration that contribute to unintended placement of the composition can lead to undesirable effects such as arachnoiditis caused from an epidural injection.
There exists a need for an improved pharmaceutical composition that can provide a quick local onset of action as well as a long lasting effect; have physical characteristics that facilitate injection into various parts of the body; and be shelf-stable. In particular, a stable, long-acting pharmaceutical composition suited for epidural, intra-articular, or intra-lesional injection is desirable.
One solution to this need was put forth in the form of a pharmaceutical composition comprising both a soluble form and an insoluble form of a corticosteroid in water (PCT International Publication No. WO 2014/116876). The soluble form of the corticosteroid offers immediate relief, whereas the insoluble form provides a longer-lasting effect. However, in 2014, the U.S. Food and Drug Administration (FDA) issued a warning that injection of corticosteroids into the epidural space of the spine may result in rare but serious adverse effects such as loss of vision, stroke, paralysis, and death. In response, 17 safety recommendations proposed by the Multi-Society Pain Workgroup (MPW) were approved, including the recommendation that particulate steroids should not be used in transforaminal injections. Transforaminal injections are attractive routes for administration of pain medication because the injection site location is closest to the presumed site of inflammation. Accordingly, there exists a need for improved pharmaceutical compositions that can provide both quick onset of action and a long lasting effect, and are approved for all three routes of injection (transforaminal, interlaminar, and caudal).